1. Field Of The Invention
This invention is in the field of pharmaceutical agents which selectively act as leukotriene B.sub.4 (LTB.sub.4) antagonists.
2. Prior Art
The prior art discloses compounds having structures similar to Formula I except in the prior art compounds R.sup.2 of Formula I is replaced with hydrogen. For example:
______________________________________ EPA 079,637 EPA 100,466.6 (U.S. Pat. No. 4,665,203) U.S. Pat. No. 4,595,882 U.S. Pat. No. 4,546,194 EPA (U.S.S.N) 507383 129,906 CA 103 (19) 160 389 G Japan 60/42378 EPA 150447 ______________________________________
Journal of Medicinal Chemistry, 1977, 20 (3) 376 broadly discloses compounds where R.sup.2 of Formula I is hydrogen.
European Pat. No. 79,637 generically discloses a formula which encompasses compounds of Formula I wherein --OR.sup.2 is --O-alkyl and B is C.dbd.O, but does not exemplify or otherwise enable the preparation and use of such compounds. European Pat. No. 79,637 extensively discloses intermediates to making compounds of this invention, that is, where --OR.sup.2 in formula I is --OH. European Pat. No. 79,637 does not teach the selective LTB.sub.4 antagonist activity of compounds of this invention.
U.S. Pat. No. 4,281,008, U.S. Pat. No. 3,822,148, and U.S. Pat. No. 4,006,245 generically disclose formulae which encompass compounds of Formula I wherein --OR.sup.2 is --O-alkyl or O--Me and B is C.dbd.O but do not exemplify or otherwise enable the preparation and use of such compounds, nor do they teach the selective LTB.sub.4 antagonist activity of compounds of the present invention.
The Journal of Medicinal Chemistry, 1977, Vol. 20 (3): 376 discloses a compound similar to the compounds of Formula I except the acyl and alkyl substituents adjacent the --OR.sub.2 in Formula I are absent. The Journal of Medicinal Chemistry article also discloses a compound similar to compounds of Formula I except for a hydroxy substituent on the --O--(CH.sub.2).sub.x --O-- connecting group.
The prior art generally describes the above compounds as LTD.sub.4 antagonists for use as anti-allergy compounds or as antagonists of SRS-A, the slow reacting substance of anaphylaxis. In sharp contrast compounds of Formula I are selective LTB.sub.4 antagonists useful in treating inflammatory diseases.
Leukotriene D.sub.4 and C.sub.4 (LTD.sub.4 /LTC.sub.4) and leukotriene B.sub.4 (LTB.sub.4) are products of the arachidonic acid metabolic pathway. LTD.sub.4 and LTC.sub.4 are associated with smooth muscle contraction and contract guinea pig ileum, human and guinea pig bronchi and human pulmonary artery and vein. LTB.sub.4 is associated with neutrophil stimulation and is characterized by chemotaxis, aggregation and degranulation. LTB.sub.4 is believed to be an important mediator of inflammation. High levels of LTB.sub.4 are detected in rheumatoid arthritis, gout, psoriasis, and inflammatory bowel disease. Thus antagonists of LTB.sub.4 are useful in the therapy of such diseases.
Gastroenterology, 1985: 88: 580-7 discusses the role of arachidonic acid metabolites in inflammatory bowel disease.
British Medical Bulletin, (1983), vol. 39, No. 3, pp. 249-254, generally discusses the pharmacology and pathophysiology of leukotriene B.sub.4.
Biochemical and Biophysical Research Communications, Vol. 138, No. 2 (1986), pp. 540-546 discusses the pharmacology of a specific LTB.sub.4 antagonist which has a different structure than compounds of this invention.